This is an application for a Texas Medical Center NIH/NIAID Asthma and Allergic Diseases Cooperative Research Center that unites the University of Texas M.D. Anderson Cancer Center and Baylor College of Medicine to investigate the role of human Thymic Stromal Lymphopoietin (TSLP) in the development and maintenance of the Th2 immune response that dominates the allergic phenotype. The proposed studies will test the overall hypothesis that TSLP is a master switch for developing and maintaining atopy and asthma. TSLP is a hematopoietic cytokine encoded on the human chromosome 5q22 cluster of Th2 cytokine genes, and in humans is produced predominately by epithelial cells and activated mast cells, and is expressed in the context of atopic dermatitis and allergic asthma. Genetically engineered murine models of allergic disease also support a central role for TSLP in the pathobiology of atopy. This proposal integrates four research projects, two research cores and an administrative core focused on TSLP. Project 1 will investigate the mechanisms for induction of TSLP expression by human respiratory epithelial cells and mast cells. Project 2 will determine the mechanisms by which TSLP activates myeloid dendritic cells. Project 3 will elucidate mechanisms by which TSLP activated myeloid dendritic cells propagate Th2 effecter and memory cells. Project 4 will focus on the role of inflammatory T helper cells (Thi) in the upregulation of TSLP production. These projects will be supported by an Administrative Core, an Analytical Research Core, and a Clinical Research Core. The proposed studies should provide new insight into the mechanisms of allergic disease and asthma, and potentially identify new targets for therapeutic intervention.